1,3-Difunctionalization of [1.1.1]propellane through iron-hydride catalyzed hydropyridylation

Current methodologies for the functionalization of [1.1.1]propellane primarily focus on achieving 1, 3-difunctionalized bicyclo[1.1.1]pentane or ring-opened cyclobutane moiety. Herein, we report an innovative approach for the 1, 3-difunctionalization of [1.1.1]propellane, enabling access to a diverse range of highly functionalized cyclobutanes via nucleophilic attack followed by ring opening and iron-hydride hydrogen atom transfer. To enable this method, we developed an efficient iron-catalyzed hydropyridylation of various alkenes for C − H alkylation of pyridines at the C4 position, eliminating the need for stoichiometric quantities of oxidants or reductants. Mechanistic investigations reveal that the resulting N-centered radical serves as an effective oxidizing agent, facilitating single-electron transfer oxidation of the reduced iron catalyst. This process efficiently sustains the catalytic cycle, offering significant advantages for substrates with oxidatively sensitive functionalities that are generally incompatible with alternative approaches. The strategy presented herein is not only mechanistically compelling but also demonstrates broad versatility, highlighting its potential for late-stage functionalization.

Current methodologies for the functionalization of [1.1.1]propellaneprimarily focus on achieving 1, 3-difunctionalized bicyclo[1.1.1]pentaneor ring-opened cyclobutane moiety.Herein, we report an innovative approach for the 1, 3-difunctionalization of [1.1.1]propellane,enabling access to a diverse range of highly functionalized cyclobutanes via nucleophilic attack followed by ring opening and iron-hydride hydrogen atom transfer.To enable this method, we developed an efficient iron-catalyzed hydropyridylation of various alkenes for C − H alkylation of pyridines at the C4 position, eliminating the need for stoichiometric quantities of oxidants or reductants.Mechanistic investigations reveal that the resulting N-centered radical serves as an effective oxidizing agent, facilitating single-electron transfer oxidation of the reduced iron catalyst.This process efficiently sustains the catalytic cycle, offering significant advantages for substrates with oxidatively sensitive functionalities that are generally incompatible with alternative approaches.The strategy presented herein is not only mechanistically compelling but also demonstrates broad versatility, highlighting its potential for late-stage functionalization.
There are two notable prior approaches to the radical hydropyridylation of alkenes via MHAT [55][56][57][58][59][60][61] .The Herzon group developed a cobalt-mediated radical hydropyridylation of alkenes using alkoxypyridinium salts and tert-butyl hydroperoxide (TBHP) 55,56 .However, employing both the stoichiometric Co and oxidant TBHP introduces complexity to the reaction, diminishing efficiency for large-scale applications.Additionally, achieving regioselective alkylation on unbiased pyridine cores is problematic due to competing sites (C2 vs C4) for radical interception.Recently, the Teskey group achieved photochemical hydropyridylation, involving dienes and pyridyl phosphonium salts with a cobalt-hydride catalyst 57 .However, due to the high reduction potential (E red = 1.51 V vs SCE) 62 of phosphonium salts, this method requires a strong reductant such as the photoactivated Hantzsch ester (E * ox = -2.28V vs SCE) 63 , which restricts its compatibility with various functional groups.Our evaluation of the proposed three-component reactions revealed that these harsh conditions adversely affected the stability of the 3-methylenecyclobutan-1-ylium cation, underscoring the necessity for milder reaction conditions.
To address this challenge, we developed a strategy utilizing N-amidopyridinium salts as versatile reagents that facilitate both the [1.1.1]propellanering-opening and hydropyridylation steps.We speculated that N-centered radicals derived from these salts [64][65][66][67][68][69] could serve as efficient oxidizing agents for the reduced state of the metal catalyst, thereby promoting the regeneration of the catalytic cycle without necessitating an external catalyst regenerator 65,69 .Subsequently, the alkyl radical intermediate, formed via iron-catalyzed HAT to the alkene, engages in a radical addition at the C4 position of N-amidopyridinium salts [70][71][72][73] .Our investigations revealed that these mild conditions offer a suitable method for hydropyridylation of the in-situ generated 3-methylenecyclobutan-1-ylium cation, which is critical for the 1, 3-difunctionalization of [1.1.1]propellane.This approach facilitates a successful three-component reaction, providing swift access to a wide array of highly functionalized cyclobutanes and accommodating a diverse range of alkenes with various functional groups (Fig. 1b).

Reaction discovery and optimization
Our preliminary results indicated that an acidic proton can be generated through the nucleophilic attack of alcohols on N-amidopyridinium salts.Focusing on the acid-mediated ring-opening of [1.1.1]propellane,we examined its reaction with N-amidopyridinium salt in MeOH.Notably, we observed a substantial conversion of propellane, which involved acid-catalyzed ring opening followed by nucleophilic addition of methoxide, leading to a new synthetic pathway to methylenecyclobutane 4a (Fig. 2).Encouraged by these findings, our next goal is to combine olefin hydropyridylation with MHAT for the alkene moiety, laying the groundwork for an efficient 1, 3-difunctionalization strategy for [1.1.1]propellane.
To achieve this objective, we initially explored the development of an efficient MHAT method for alkenes, tailored to operate under mild conditions.This approach was specifically designed to be compatible with the unstable cation intermediate generated from [1.1.1]propellane.The characteristics of N-amidopyridinium salts and the efficiency of amidyl radicals are greatly influenced by the electronic and steric properties of the N-substituents.Therefore, we initially screened various N-substituents, with a focus on the in-situ generation of amidyl radicals and a catalyst regeneration strategy (Table 1).
Our screening identified N-amidopyridinium salts with a tosyl group as having the highest reactivity.Building on this, we further tested N-amidopyridinium salts 2a and alkene 5a (Supplementary Table 1).By employing Fe(acac) 3 , we achieved an 82% yield in the hydropyridylated product 6a, exhibiting exclusive regioselectivity for both the Markovnikov addition on the alkene and the C4 position of pyridine (entry 1).We observed that bulkier Fe(III) catalysts such as Fe(dpm) 3 and Fe(dibm) 3 were less efficient, likely due to hindered interaction with the amidyl radical (entry 2).Meanwhile, Fe(II) catalysts demonstrated moderate reactivity (entry 3), with a slight decomposition of N-amidopyridinium salt under the reaction conditions.Cobalt and manganese catalysts, although frequently used in MHAT reactions [46][47][48] , showed less than 10% reactivity, making them unsuitable for this reaction (entry 4).When testing different alcohols, MeOH exhibited reactivity comparable to EtOH, while i PrOH showed a decrease in reactivity, attributed to lower salt solubility (entry 5).The employment of PhSiH 3 led to a modest reduction in reactivity, achieving a yield of 58% (entry 6) 74 .The presence of oxygen, which  typically aids in Fe catalyst regeneration 75,76 , severely impeded the reaction at high concentrations, leading to only trace amounts of the desired product.Likewise, a substantial decrease in reactivity was also observed under air conditions (entry 7).Control experiments conducted without the Fe catalyst or silane failed to produce any hydropyridylated product, underscoring the essential roles of these components (entry 8).The fact that the reaction proceeds in the absence of an external base, achieving a 43% yield (entry 9), suggests that the in-situ generated amide or pyridine may serve as the base.Building upon hydropyridylation reaction conditions, we then continue the optimization of the 1, 3-difunctionalization of [1.1.1]propellane,focusing on reactions involving the 3-methylenecyclobutan-1ylium cation.The reaction with EtOH as solvent and reactant, 1, 3-difunctionalized cyclobutane product 3a was obtained with 73% yield (d.r.= 3.0: 1) (entry 10) 77 .Even when using the Fe catalyst with a bulky ligand, there is little change in diastereoselectivity, suggesting that the Fe catalyst has no influence on the radical insertion process of the N-amidopyridinium salt (entry 11).During the optimization process, we noted variations in MHAT selectivity (alkene vs. [1.1.1]propellane)contingent upon the base used.For example, employing NaOAc as the base resulted in predominantly the formation of hydropyridylated BCP through direct MHAT of [1.1.1]propellane(entry 12).Similar to the hydropyridylation, a slight decrease in reactivity was observed in the absence of base (entry 13).

Substrate scope studies
Leveraging these optimized conditions, we initiated a comprehensive investigation into the scope of alcohols, particularly emphasizing those commonly utilized as solvents (Fig. 3).Our findings indicate that primary alcohols exhibit outstanding reactivity under these conditions (3a, b).Expanding our scope to include secondary alcohols, we encountered solubility issues with the N-amidopyridinium salt, necessitating the introduction of a co-solvent system with dichloromethane (DCM).To our delight, in this slightly modified system, both acyclic (3c) and cyclic (3d) secondary alcohols displayed robust reactivity.Although tertiary alcohols exhibited a decreased reactivity, a consequence of their reduced nucleophilicity, they nonetheless participated in the reaction with reasonable efficacy (3e, f).Notably, the method showed remarkable compatibility with structurally intricate alcohol solvents, such as ethylene glycol ether, maintaining efficient reaction progress (3g, h).Moreover, the versatility of the pyridine core was explored using pyridines with various substituents at the C2 or C3 positions.A diverse array of pyridines, including aryl (3i-3k), heteroaryl (3l), trifluoromethyl (3m), cyano (3n), methyl (3o-q)substituted variants, consistently yielded 1, 3-difunctionalized products.In addition, the reaction also efficiently accommodated unsubstituted pyridine (3r), achieving effective ring opening and demonstrating the method's broad tolerability.Pleasingly, 1,3-difunctionalization was also applicable to pyridine-based pharmaceuticals such as vismodegib (3s), bisacodyl (3t), and pyriproxyfen (3u) moieties.
Building upon our understanding of the 1, 3-difunctionalization reaction, we speculated that the use of a catalytic amount of N-amidopyridinium salt would facilitate the synthesis of methylenecyclobutanes featuring a broad range of alcohol integrations.The study yielded impressive results: primary (4a, b), secondary (4c), and tertiary alcohols (4d), as well as ethylene glycol ether (4e), all showed significant reactivity.Notably, the reaction involving benzyl alcohol stood out, delivering a high yield and highlighting its potential as a preferred reactant for methylenecyclobutane production (4f).This methodology has proven to be highly effective, producing an array of ether-containing methylenecyclobutanes.Collectively, these findings highlight the robustness and versatility of method, paving the way for diverse applications in the realm of complex molecule synthesis.
To further demonstrate the practical applicability of our developed methodology, we conducted a series of experiments focused on the late-stage functionalization of complex bioactive molecules (Fig. 5).We were pleased to discover that our method efficiently transformed alkene derivatives derived from fenofibrate (8a), zaltoprofen (8b), tyrosine (8c), and D-glucal (8e) into their corresponding hydropyridylated products under standard conditions.Notably, even eugenol (8d), which possesses a redox-active phenol group, yielded the desired product satisfactorily.The versatility of our approach was further highlighted by its successful application in the functionalization of structurally complex molecules, including steroids and terpenoids, exemplified by estrone (8 f), boldenone undecylenate (8 g), and citronellol (8 h).Additionally, our method exhibited remarkable selectivity in modifying complex pyridine moietries (8i-k).These results significantly expand the scope of our synthetic method, underscoring its potential for the selective modification of pharmacologically relevant compounds.

Control experiments and proposed mechanism
To gain detailed insights into the mechanism of 1, 3-difunctionalization of [1.1.1]propellaneand hydropyridylation, various mechanistic studies were conducted (Fig. 6).Initially, to ascertain the role of the N-amidopyridinium moiety in facilitating ring opening, we performed control experiments.These experiments demonstrated that, in the presence of N-amidopyridinium salt 2a, the methylenecyclobutane product 4e was synthesized with a 54% yield.Conversely, the absence of N-amidopyridinium salt or the inclusion of NaBF 4 as an additive resulted in only trace yields of product 4e.This finding prominently highlights the critical role of the N-amidopyridinium salt in enabling the ring opening of [1.1.1]propellane,as illustrated in Fig. 6a.Then, deuterium labeling experiments were carried out to elucidate the ringopening step of [1.1.1]propellane.Upon changing the reaction solvent MeOH to CD 3 OD, 99% deuterium incorporation was observed at the oxygen α-position of the product (Fig. 6b).This result confirmed that the acidic proton used in the ring-opening step is derived from the proton in the alcohol solvent.When the reaction was conducted with a C4 blocked pyridinium salt 2n, we observed the formation of methylenecyclobutane 4b; however, the product resulting from insertion at C2, 3 v, was not detected (Fig. 6c).This indicates that the N-substituent effectively inhibits radical insertion at the C2 position.Next, in the hydropyridylation of the alkene, we sought to confirm the involvement of a radical pathway through MHAT.The reaction was conducted under optimized conditions using vinylcyclopropane (5ax) and hepta-1,6-diene (5ay) (Fig. 6d).The results revealed the occurrence of both ring opening (6ax) and ring closing (6ay), indicating the generation of a Markovnikov-selective radical.Furthermore, when the radical scavenger TEMPO was added as an additive and the reaction proceeded, the desired product was not formed at all, and alkyl radical-TEMPO adducts were observed in the HRMS (Fig. 6e).
On the basis of these mechanistic studies, we propose a mechanism for the 1,3-difunctionalization of [1.1.1]propellaneand hydropyridylation of alkenes (Fig. 6f).The nucleophilic attack of alcohol on N-amidopyridinium salt A generates the acidic oxonium cation B (Part A) 88 .The propellane is subsequently protonated by the acidic proton of oxonium cation B, triggering a rearrangement that yields unstable cation D. Concurrently, the generated cation D is subjected to alcohol insertion, culminating in the formation of intermediate E [33][34][35][36][37][38][39][40][41][42][43][44][45] .Following this, intermediate E may partake in a proton exchange with intermediate C or initiate a chain reaction pathway by protonating [1.1.1]propellane,ultimately yielding methylenecyclobutane F. Control experiments with propellane revealed that methylenecyclobutane F is produced in ~9% yield with Fe(II) or Fe(III) (See the SI for details), even when N-amidylpyridinium salt is not present.This result indicates that the pathway culminating in the iron carbene complex G likely functions as a minor route in these reactions.The methylenecyclobutane F is subsequently utilized in the ongoing hydropyridylation process (Part B).During this phase, the FeX 3 (III) undergoes solvolysis with alcohol, leading to the formation of the activated FeX 2 OEt(III) catalyst 74 .Following this, the hydride/alkoxy exchange with silane gives rise to the formation of FeX 2 H(III).The iron hydride then interacts with alkenes F or H via MHAT, generating the Markovnikov-selective alkyl radical intermediate I.This alkyl radical I undergoes radical insertion into the C4 position of N-amidopyridinium salt A, followed by deprotonation, to yield the desired product K along with the formation of the amidyl radical J.The amidyl radical J then acts as an oxidant, facilitating the regeneration of FeX 2 OEt(III) from FeX 2 (II), thereby completing the catalytic cycle.

Discussion
In summary, we have successfully developed a highly efficient, ironhydride catalyzed Markovnikov/C4 selective hydropyridylation of alkenes, operable under mild conditions.Our groundbreaking technique overcomes previous challenges by leveraging N-centered radicals derived from N-amidopyridinium salts as efficient oxidizing agents.This innovation not only streamlines the catalytic cycle but also exhibits broad compatibility with various functional groups, including those sensitive to oxidation.Significantly, we have adeptly extended this hydropyridylation method to the 1, 3-difunctionalization of [1.1.1]propellane, facilitating the synthesis of intricate cyclobutanes via a three-component reaction.This method integrates diverse alcohols and pyridines, showcasing a distinctive mechanistic pathway and underscoring its potential for late-stage functionalization of complex, biologically relevant molecules.Overall, this study presents a robust, versatile, and sustainable methodology, setting the stage for transformative advancements in the functionalization of alkenes and [1.1.1]propellane.

Fig. 6 |
Fig. 6 | Experimental mechanistic investigations and proposed mechanism.a Control experiment of [1.1.1]propellanering opening.b Deuterium labeling experiment.c C4-blocked pyridine experiment.d Radical clock experiment.e Radical capture experiment.f Proposed mechanism.